This is a competing renewal of a multidisciplinary research program project for the study of the clinical, molecular genetic, physiologic and pathologic aspects of Rett syndrome (RS). Over the past 10 years the research activities of this Center resulted in the definition of the unique clinical phenotype of RS, suggested the neurodevelopmental nature of RS, and broadened our hypotheses regarding genetic models. A large cohort of patients has been characterized and enrolled in the various research protocols which led us to classify RS as a developmental disorder. This assessment is a departure from the initial interpretation of RS as being a progressive, degenerative disease and led to the genesis of the following hypotheses which will be addressed in this renewal application: (1) RS is either X-linked or autosomal dominant with sex limited expression. (2) RS is the result of a selective arrest of brain development. (3) The developmental arrest in RS results from a deficiency of the neurotropic activity of neurotransmitters, particularly monoamine and GABAergic neurotransmitters. (4) The arrest of brain development in RS is associated with impaired maturation and growth of the whole body, as well as specific systems such as the cardiac conduction system. Project 5 will investigate candidate genes on the X-chromosome for mutations; complete genetic mapping studies in familial cases; use representational difference analysis to identify new mutations in the genomic DNA of RS; and characterize sexually-dimorphic genes expressed in the CNS. Project 6 will study the features in brain and heart which suggest developmental arrest using morphology, immunocytochemistry and quantitation of neurotransmitter receptor binding densities. Project 8 will characterize the morphology, maturation, and chemoarchitecture of the nervous system deprived of the trophic effects of monoamines, with emphasis on developing a neuropathologic model of RS. Project 7 will assess somatic growth failure in RS by evaluating the mechanisms by which the partitioning of protein and calcium balance is altered using stable isotope techniques. These projects are served by the Core which is the Center for patient identification, education, follow-up, and research protocol enrollment. The Core integrates research activities, provides statistical design and analysis support, and continues to develop an already extensive data base that is not only used regularly for patient identification and selection, but also for the generation of hypotheses. The Baylor College of Medicine Rett Center brings together a multidisciplinary team to study in an integrated fashion the many dimensions of this enigmatic disorder.